POS0519 RELATIONSHIP BETWEEN DISEASE ACTIVITY AND MAJOR ADVERSE EVENTS IN PATIENTS WITH RHEUMATOID ARTHRITIS ON TOFACITINIB OR TNF INHIBITORS: A POST HOC ANALYSIS OF ORAL SURVEILLANCE
Authors: G. Karpouzas, Z. Szekanecz, E. Baecklund, T. Mikuls, D. L. Bhatt, H. Shi, C. Wang, G. Sawyerr, Y. Chen, S. Menon, C. A. Connell, S. R. Ytterberg, M. Mortezavi
Journal: Annals of the Rheumatic Diseases (2022)

Background Uncontrolled rheumatoid arthritis (RA) activity and acute disease flares are associated with higher risk of adverse outcomes such as cardiovascular (CV) disease, venous thromboembolism (VTE), malignancy and infection. 1-4 Objectives To evaluate associations of acute and cumulative Clinical Disease Activity Index (CDAI) measurements with major CV, malignancy, or infectious adverse events (AEs) of special interest in ORAL Surveillance. Methods ORAL Surveillance ( NCT02092467 ) was a post-authorisation safety study of tofacitinib vs TNF inhibitors (TNFi) in patients (pts) aged ≥50 yrs with active RA despite methotrexate (MTX), and ≥1 additional CV risk factor. Pts were randomised 1:1:1 to tofacitinib 5 or 10 mg twice daily (BID) or subcutaneous TNFi. Two post hoc analyses were performed: (1) a time-varying multivariate Cox model examined risks of major AEs when pts were in CDAI-defined low (&gt;2.8–≤10; LDA), moderate (&gt;10–≤22; MDA) or high (&gt;22; HDA) disease activity vs remission (≤2.8). The Cox model also included pt demographics, medical history, RA characteristics, prior treatments, baseline (BL) medications and treatment arm, pre-selected using backward selection; (2) area under the curve (AUC) per yr for CDAI prior to event or to study end (pts without event) was calculated and compared using an analysis of variance model with treatment arm, event status and interaction (supportive). Nominal p values &lt;0.10 were considered evidence of associations. Results 4362 pts were included. Mean RA duration at BL was approximately 10 yrs. All pts were on MTX at BL, and 28% had previously been on one other synthetic disease-modifying antirheumatic drug (DMARD). Overall, 10% of pts had been on one biologic DMARD. Hazard ratios suggested that when pts had LDA, MDA or HDA vs remission, they were potentially at higher risk of developing major adverse CV events (MACE), VTE and non-serious infections (NSIs) excluding herpes zoster (HZ), but not malignancies, serious infections or HZ (Figure 1). Similarly, mean CDAI AUC trended higher for MACE, VTE and NSIs (Table 1). Table 1. Cumulative CDAI (from BL to event) for pts with vs without events (AUC/yr) Major AE Pts with events Pts without events LS mean difference in pts with vs without events p value Treatment n LS mean AUC/yr n LS mean AUC/yr MACE Tofacitinib 5 mg BID 42 6275.4 1336 4607.3 1668.1 0.0018 * Tofacitinib 10 mg BID 50 5237.4 1306 4482.6 754.8 0.1253 TNFi 36 5234.5 1312 4851.5 383.0 0.5069 VTE Tofacitinib 5 mg BID 15 6546.7 1363 4614.4 1932.3 0.0293 * Tofacitinib 10 mg BID 31 6688.2 1323 4458.5 2229.7 0.0003 * TNFi 8 6423.6 1339 4839.4 1584.1 0.1907 Malignancy excl. NMSC Tofacitinib 5 mg BID 59 5249.3 1319 4618.9 630.4 0.1655 Tofacitinib 10 mg BID 55 4793.7 1301 4482.2 311.5 0.5077 TNFi 39 5561.4 1308 4826.3 735.1 0.1854 Serious infections Tofacitinib 5 mg BID 127 5710.2 1242 4577.5 1132.7 0.0004 * Tofacitinib 10 mg BID 150 5425.2 1197 4476.4 948.8 0.0013 * TNFi 105 6058.4 1240 4807.7 1250.7 0.0003 * HZ Tofacitinib 5 mg BID 175 5184.5 1199 4738.1 446.4 0.1101 Tofacitinib 10 mg BID 163 5549.1 1186 4481.3 1067.8 0.0002 * TNFi 56 5667.2 1291 4875.5 791.8 0.0930 * NSIs excl. HZ Tofacitinib 5 mg BID 760 6608.3 463 5122.5 1485.8 &lt;0.0001 * Tofacitinib 10 mg BID 750 6587.8 426 5009.6 1578.2 &lt;0.0001 * TNFi 722 6737.6 521 5217.5 1520.1 &lt;0.0001 * * p&lt;0.10. Data collected after pts who were randomised to tofacitinib 10 mg BID had their dose reduced to 5 mg BID were included in the tofacitinib 10 mg BID group LS, least squares; n, number of pts in analysis of variance model Conclusion In ORAL Surveillance, the risk of MACE, VTE and NSIs excluding HZ appeared higher when pts had active disease than when in remission. Greater cumulative RA disease activity was seen in pts who suffered these AEs vs those who did not. Our findings support treat-to-target recommendations for RA. References [1]Molander et al. Ann Rheum Dis 2021; 80: 169-175. [2]Maradit-Kremers et al. Arthritis Rheum 2005; 52: 722-732. [3]Au et al. Ann Rheum Dis 2011; 70: 785-791. [4]Baecklund et al. Arthritis Rheum 2006; 54: 692-701. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by Karen Thompson, PhD, CMC Connect, and funded by Pfizer Inc. Disclosure of Interests George Karpouzas Speakers bureau: Sanofi-Genzyme-Regeneron, Consultant of: Janssen and Sanofi-Genzyme-Regeneron, Grant/research support from: Pfizer Inc, Zoltán Szekanecz Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Paid instructor for: AbbVie, Eli Lilly, Gedeon Richter, Novartis, Pfizer Inc and Roche, Consultant of: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Eva Baecklund: None declared, Ted Mikuls Paid instructor for: Pfizer Inc, Consultant of: Gilead Sciences, Horizon and Sanofi, Grant/research support from: Bristol-Myers Squibb and Horizon, Deepak L Bhatt Grant/research support from: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Eli Lilly, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Medtronic, MyoKardia, Novo Nordisk, Owkin, Pfizer Inc, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic and The Medicines Company, Harry Shi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cunshan Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Gosford Sawyerr Consultant of: Pfizer Inc, Employee of: Syneos Health Inc, Yan Chen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Sujatha Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Carol A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Steven R. Ytterberg Consultant of: Corbus Pharmaceuticals, Kezar Life Sciences and Pfizer Inc, Mahta Mortezavi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc.